Research

Nebulized antithrombin limits bacterial outgrowth and lung injury in Streptococcus pneumoniae pneumonia in rats

Jorrit J Hofstra^1,2,3 , Alexander D Cornet^1,4 , Bart F de Rooy⁵ , Alexander P Vlaar^1,2,6 , Tom van der Poll^6,7,8 , Marcel Levi⁶ , Sebastian AJ Zaat^5,8 and Marcus J Schultz^1,2

¹Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands

²Department of Intensive Care Medicine, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands

³Department of Anesthesiology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands

⁴Department of Intensive Care Medicine, Vrije Universiteit Medical Centre, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

⁵Department of Medical Microbiology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands

⁶Department of Internal Medicine, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands

⁷Centre for Experimental and Molecular Medicine (CEMM), Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands

⁸Centre for Infection and Immunity Amsterdam (CINIMA), Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands

author email corresponding author email

Critical Care 2009, 13:R145doi:10.1186/cc8040

Published:	9 September 2009

Abstract

Introduction

Disturbed alveolar fibrin turnover is a cardinal feature of severe pneumonia. Clinical studies suggest that natural inhibitors of coagulation exert lung-protective effects via anticoagulant and possibly also anti-inflammatory pathways. Intravenous infusion of the natural anticoagulants increases the risk of bleeding. Local administration may allow for higher treatment dosages and increased local efficacy while at the same time reducing the risk of bleeding. We evaluated the effect of nebulized anticoagulants on pulmonary coagulopathy and inflammation in a rat model of Streptococcus pneumoniae pneumonia.

Methods

In this randomized controlled in vivo laboratory study rats were challenged intratracheally with S. pneumoniae, inducing pneumonia, and randomized to treatment with normal saline (placebo), recombinant human activated protein C (rh-APC), plasma-derived antithrombin (AT), heparin or danaparoid, by means of nebulization.

Results

S. pneumoniae infection increased pulmonary levels of thrombin-antithrombin complexes and fibrin degradation products. All nebulized anticoagulants significantly limited pulmonary coagulopathy. None of the agents except danaparoid resulted in changes in systemic coagulopathy. Treatment with plasma-derived AT reduced outgrowth of S. pneumoniae and histopathologic damage in lungs. In vitro experiments confirmed outgrowth was reduced in bronchoalveolar lavage fluid (BALF) from rats treated with plasma-derived AT compared with placebo. Neutralizing of cationic components in BALF diminished the inhibitory effects on bacterial outgrowth of BALF, suggesting a role for cationic antimicrobial proteins.

Conclusions

Nebulization of anticoagulants attenuates pulmonary coagulopathy during S. pneumoniae pneumonia in rats while only danaparoid affects systemic coagulation. Nebulized plasma-derived AT reduces bacterial outgrowth and exerts significant lung-protective effects.